IL32893A - Dosage unit forms of prostaglandins and uses thereof - Google Patents

Description

DOSAGE UNIT FORMS OF PEOSTAGIA DINS AND USES THEREOF \ ABSTRACT OF THE DISCLOSURE Methods and 6omposi tions for administering prostaglandins of the PGF type to ovulating female mammals including animals and humans in the control of the reproductive cycle.

BRIEF SUMMARY OF THE INVENTION This invention relates to mothodo- and compositions for controlling the reproductive cycle in ovulating female mammals including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. PGF-type prostaglandins in dosage unit forms of pharmaceutical preparations are administered systemically to the female mammals, the preparations supplying an effective amount for control ling the reproductive cycle of a member selected from the group consisting of the free acids, pharmaceutically acceptable salts, acylates wherein the acyl radical is that of a hydrocarbon carboxylic acid having 1 to 8 carbon atoms, inclusive, and carboxylate esters having 1 to 8 carbon atoms, inclusive, of a compound represented by the formula wherein X is CH2CH2 or trans CH=CH and both Y and Z are CH2CH2; X is trans CH=CH, Y is cis CH=CH and Z is CH2CH2 or cis CH=CH; m is 0, 1 or 2 and n is 2, 3, 4 or 5.

DETAILED DESCRIPTION A crude mixture, called prostaglandin was reported by von Euler, Arch. Exp. Path, Pharm Abs. 175,78 (1934); 181 (1936); J. Physiol 72,74 (1931); 81,102 (193 ); 84,21 (1935) 88,213 (I936); and Klin. Wschr 14, 1182 (1935). More recently essentially pure crystalline PGF (PGFi or PGFi ) has been isolated, British Patent 851,827 and Acta Chemica Scandinavica fatty acids with mammalian glandular tissue are described in U.S. Patents No. 3, 290, 226 and 3, 296, 091. in the latter patent PGF (PGFi or PGFia) is designated as 7- [ 3a, 5a-d i hydroxy- 2- ( 3-hydroxy- 1-octentyl ) - cycl openty 1 ]-heptanoic acid to conform to the following structure: The PGF-type prostaglandins are characterized by the presence of the hydroxyl group at the 5-position in the cyclopentane ring. The designation PGFia shows the configuration of the hydroxyl at the 5-position. Various other members of the PGF- type are known and are named either systematically or in terms of their relationship to PGF. Illustrative thereof are PGF2a or 7" [ 3a-5a- di hydroxy- 2- ( 3- hydroxy- 1-octenyl ) -cycl opentyl ] - 5~heptenoi c acid, PGF3C. or J-Ja, 5a-d i hydroxy- 2- ( 3_ hydroxy- 1, 5-octad i eny 1 ) -cyclopentyl ] - 5-heptenoic acid, and dihydro PGFia or 7~ [ 3a, 5a-di hydroxy- 2- ( 3-hydroxy-octyl )-cyclopentyl 1 heptanoic acid.

Details of preparations from available materials are disclosed for dihydro PGFia, PGF2a, and PGF3a in Biochimica and Bio-physica Acta, 84, 7 7 ( 1964 ) , and for PGFia in U. S. 3, 069, 322. Bergstrom, Carlson and Weeks, Pharmacological Reviews, Vol. 20, No. 1, I892 ( 1968) review "The Prostaglandins".

Pharmaceutically acceptable salts for example, those of alkali metals and alkaline earth bases, such as the sodium, potassium, calcium and magnesium salts; those of ammonia or a basic amine such as mono-, di-, and triethyl amines, benzylamine, heterocyclic amines such as piperidine and morpholine, and amines containing water-solubi 1 i zing or hydrophilic groups such as triethanol amine and pheny lmonoethanol ami ne are disclosed in U. S. 3*296,091. Carboxylate esters such as methyl, ethyl, cyclohexyl and the like having no more than 8 carbon atoms are formed by the usual methods, e.g., reaction with diazomethane or similar di azohydrocarbons as in U. S. 3*296,091. Acylates of lower alkanoic acids of 1 to 8 carbon atoms inclusive are prepared in the usual manner by reaction of the respective prostaglandin acids with the appropriate acid anhydride or acid halide, e.g., those of acetic, propionic, butyric, isobutyric, valeric, caproic, caprylic and the like acids, as in Great Britain Patent Specification No. 1,0 0, .

It is especially advantageous to formulate the inventive compositions in dosage unit forms for ease and economy of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means. The specif i-cations for the novel dosage unit forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular biological effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for administration to animal and human subjects as disclosed in detail in this specification, these being features of the present invention. i llustrati ely, effectiveness of the pharmaceutical preparations and methods of administration in the human female is dependent on providing thereto a,n effective amou rit of the active ingredient during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Within this span wherein the preparations and methods are operable, variations in time and frequency of administration are possible provided an effective amount of the essential active ingredient is made available. This span correlates with development of the corpus luteum upon which, according to some experimental data, a luteolytic effect is exerted by the present prepa-rations and methods. In harmony with the concept of administering to the female subject such an effective amount of the prostagland i n-type ingredient in the dosage unit form of pharmaceutical preparation various embodiments are possible. Illustratively, da i 1 y i nt ravenous infusion of a sterile aqueous pharmaceutical preparation containing the aforesaid active ingredient starting on or about the sixteenth day of the cycle and ending on or about the last day or two of the cycle is an effective mode of administration. This mode may be varied to allow for infusion of larger amounts on each of two or three days. Infusion admi istration on the second or third day prior to expected menses can be used. Another embodiment is a sterile pharmaceutical unit dosage preparation in an aqueous or oily vehicle form injected over a schedule of about one injection on each of two or three days. A further embodiment is a steri le aqueous suspension of a carboxylate ester as heretofore described or an acylate as heretofore described. In this embodiment one injection on or about the sixteenth or seventeenth day of the cycle is effective to bring about menses in the ovulating female at the usual time although sexual exposure occurs at the time of ovulation. Another an intravaginal suppository administered once every three days starting on or about the seventeenth day of the cycle unti l the ensuing menses appears. Yet another embodiment is a pharmaceutical preparation adapted for sublingual or buccal administration whereby the principal active ingredient is directly available to the blood supply and thereby exerts its beneficial effect. One such pharmaceutical preparation held under the tongue until dissolved once or twice dai ly starting on or about the seventeenth day of the cycle is effective to maintain the required amount of the active prostaglandin type ingredient to prevent pregnancy during the particular cycle although ovulation and exposure to the male have occurred. Other i njectab les are, for example, combinations of a water soluble salt and an acylate or carboxylate ester to provide both immediate and prolonged action. A dry preparation for reconst i tut i on as desired with an appropriate liquid, e.g. sterile saline is yet another embodiment.

The aforesaid prostaglandins are administered in dosage unit forms of pharmaceutical preparations supplying to the treated female mammal an effective amount of the essential active ingredient for control of the reproductive cycle, i .e. by ensuring a nonpregnant cycle in the female notwithstanding ovulation and contact with a fertile male as by natural coitus during the aforesaid span extending from on or about the time of ovulation to just prior to expected menses. Additionally, the ovulating female obtains regularity of the reproductive cycle by uti lizing the preparations and methods of this invention, apparently due to aiding the natural cycle regression of the corpus luteum. The preparation can be in the form of a fine powder of about 25 microns or less, preferably prepared by air micronization, such powder being used as a nasal snuff or a vaginal insufflation. The powder can be suitably compounded with a compatible extender, e.g., lactose. Other pharmaceutical preparations in dosage unit form are compounded of the essential prostaglandin active ingredient and pharmaceutical means which adapt the preparation for systemic administration. The pharmaceutical preparations for administration to the humans and animals include those for injectable, nasal, sublingual, or buccal and vaginal administration. Those for injectable administration are, for example, sterile aqueous solutions, sterile aqueous suspensions, steri le oily solutions or suspension^ sterile powders for subsequent incorporation into an injectable form by addition of the required steri le vehicle, and the like. The solutions or suspensions are compounded with the required pharmaceutical means such as preservati es, suspending and dispersing agents, and isotonic agents, for example, methyl and propyl parabens, sodium chloride, polyethylene glycols, especial ly polyethylene glycol 4000, sodium carboxymethy 1-cellulose, sodium alginate or polyvinyl pyrrolidone, poly sorbate 80, condensation products of ethylene oxide with fatty acids, for example pol yoxyethy lene stearate; or with fatty alcohols, for example heptadecaethy leneoxycetanol , or with partial esters, for example pol yoxyethylene sorbitol mono-oleate or hexitans derived from sorbitol, for example pol yoxyethylene sorbitan mono-oleate. Preservative means such as methyl and propyl p-hydroxy benzoates are incorporated into such suspensions or dispersions. Suspensions in oi ly media can be prepared by dispersing the active ingredient in an acceptable oily means, for example a vegetable oil such as sesame oil, peanut oil and cottonseed oil. These may contain means to delay absorption, for example aluminum monostearate. All dosage unit forms for injectable administration must be sterile as is known and practiced in the art.

Pharmaceutical preparations for nasal administration also include sprays formulated with acceptable aqueous means, for example a buffered isotonic aqueous vehicle containing appropriate buffer salts and, for example, lactose or mannitol. The sprays can be compounded with means adapted to form an aerosol, for example, nontoxic propel 1 ants such as the known fluorinated methane and ethane. Preparations for vaginal application include the essential active ingredient reduced in particle size to a powder suitable for insufflation or suitably mixed with inert excipient means such as lactose. Such preparations also include suppositories and other formed structures such as ring devices for intravaginal use containing the essential active ingredient, for example a silicone polymer device in the form of a toroid which will release the essential active ingredient during a predetermined period of time. The amount of the essential active ingredient provided by the various dosage forms is sufficient to supply a dosage of from about 0.01 mg. to about 20 mg. per kilo of the treated host, depending on the desired promptness, duration and magnitude of the end result. The amount of the prostaglandin compound in the several embodiments of the invention, whether for oral, injectable, or intravaginal administration can be expressed in percentage by weight or in specific amounts. These percentages or specific amounts will vary in view of the different onset and duration of the biological effects that attend each dosage unit form. For example, a sterile aqueous suspension designed for prolonged action after one injection can contain as much as 0$ by weight whereas a sterile aqueous solution as diluted with sterile sal ine for infusion can contain, as l ittle as 0.00005$ (0.5 nig. in a 1000 ml. infusion equivalent to 0.01 mg./kilo for a 0 kilogram woman). A sterile aqueous solution for direct intravenous administration, without dilution as with physiological saline can contain for example, $ or more. Dosage unit forms such as the subl ingual and intravaginal types can contain as much as 200 mg. and 500 mg. respectively. Other embodiments within the inventive concept, such as oily preparation, dry preparations for suspension and solution, are designed to provide the aforesaid dosages of from about 0.01 mg. to about 20 mg. per kilo of body weight.

Although the exact mechanism of action of the essential active ingredient of the prostaglandin type in controlling the reproductive cycle is not certain, the action manifests itself in several ways, for example, by regulating menses or heat so that the length of the cycle conforms to a predetermined span; by preventing reproduction despite ovulation and natural exposure to sperm; and by a luteolytic phenomenon involving regression of corpora lutea. This phenomenon wil l terminate anestrus.

The mechanism of action of the prostaglandins in the treated females is a matter for conjecture although experimental data indicate that a luteolytic mechanism and regression of the corpus luteum may be involved. A pharmaceutical preparation is made up by dissolving PGFaa in physiological saline at a concentration of 125 meg. /ml. and adjusting the pH within the range of to 7 with bicarbonate buffer. Cycl ing normal rats (200 to 500 gm. ) are prepared with a right uterine cornea indwell ing cathete , Weeks and Davis, J. Appl. Physiol. JLg, ^0 (1964). At the third normal proestrus pseudopregnancy is induced by vaginal stimulation with an electric probe. Vaginal smears are taken to confirm pseudopregnancy . On the morning of day 5 of pseudo-pregnancy the pharmaceutical preparation of PGF2 is infused at the rate of 2.06 ml . day equivalent to about 1 mg./kg./day of the PGF20;. The infustions of the PGF2ct preparation and a l ike saline control are continued for 8 hours at which time the animals are sacrificed and the ovaries harvested and placed in 1 ml . of 2.5$ NaOH solutions for determination of progesterone and 20a-0H progesterone. The determinations in two experiments are as l isted in Table 1.

Table 1 The Effect of PGF201 Infusion on the Concentration o and 20aOH-Proqesterone in the Ovaries of Pseudopr Ovar i an Total Locat i on W ice ii gyhntL Sample T reatment No. Ovaries (side) (mgs) ( Experiment 1 1 Saline (2.06 ml ./ 2 Right 7O.O 2 day) infused into 2 Left 67-3 right uterine horn Experiment 2 *Average values for each group The data show that the effect of the PGF2a administration is a reduction of progesterone content and an increase in the reduced steroid content, thus indicating a li^teolytic action through failure of effective progesterone content.

The following preparations and methods describe the manner and process of making and using this invention and are to be construed as exemplary embodiments of the inventive concept and not as limitations thereof.

Example 1 Intravenous infusion of pharmaceutical preparation PGF2a is made up in sterile saline solution at a concentration of 0.5 mg./ml . and used for administration by infusion in female rats. Spartan Sprague-Daw ley rats are used. Males are experienced breeders and females (22 -27 gm. body wt . ) have typical vaginal estrus cycles. Indwel ling right heart cannulas are inserted during proestrus. After cannulation, dai ly vaginal smears are again taken to insure maintenance of normal cyclicity. Initially infusion of PGF2 (3.2 mg./kg./ day in saline) commences at 4:00 p.m. the afternoon before mating and continues for six additional days. The starting time of the infusion is later modified to commence on the morning following mating because of an adverse affect on mating behavior of the environment associated with the infusion equipment. The day of finding sperm in the vacjina is considered Day 1 and the males are removed from the females at this time.

On Day 8, an exploratory laparotomy is performed under ether anesthesia via an abdominal midline incision. Uteri are checked for number, .size, and distribution of implantation sites taking care to minimize any handling of the reproductive tract. Incisions are closed wi th surgical s i 1 k, and animals returned to their original cages. On Day 18 females are placed in casting boxes. At parturition or on Day 25 animals are sacri iced and the number and condition of the young are determined.

Resu Its: Six of eight rats infused with saline only conceive. Those animals average 11.7 implantation sites at Day 8, and 7.8 develop fetuses.

Three of 11 PGF2« treated rats conceive. Implantation sites of one of these three are barely detectable at Day 8, no indication of pregnancy is evident at autopsy on Day 23. The remaining two have implants of normal size, on the low side of the average number and, in one rat, are predominately in the anterior half of the uterine cornu. Five fetuses at term appear normal by gross inspection.

Example 2 Subcutaneous administration of pharmaceutical preparat i on Prostaglandin (PGF2a) is made up in sterile saline solution at a concentration of 0.8 mg./ml. and used for subcutaneous administration in female rats. Spartan Sprague-Dawley rats are used. Males are experienced breeders and females (225-275 gm.) have typical estrous cycles. Males are placed with females during proestrus and allowed to remain overnight. The following morning females are examined for vaginal plugs and the presence of sperm. Animals with vaginal sperm are started on test, the day of finding sperm being considered Day 1.

A. 3. mg./kg. of PGF2a is injected subcutaneous 1 y daily in two evenly divided dosages. Animals are sacr i f i ced on Day 8 at which time the number and size of implants are recorded. The results are in Table 2.

B. Females are injected subcutaneous 1 y, b.i.d., on At the time of sacrifice the number, size and distribution of implants are recorded. The results are in Table 3.

- - Table 2 Effect of PGFga, Injected Subcutaneous 1 y Treatment Dose b . i .d . Days Total Dose No. 1 njected (mg)-No. of I rats Physiological Sa 1 i ne 0.5 cc Day 1-7 0.0 (5) 0.4 mg/0.5cc Day 1-7 5.6 (5) Day 3-7 4.0 (4) e CM lDay es -7 2.4 (4) a.

Day 6-7 1.6 (4) Day 6 0.8 (2) Day 7 0.8 (2) » Day 1-7 5.6 (3) β Day 1-5 4.0 (4) Day 1-3 2.4 (4) Day 2-4 2.4 (4) Day 3 0.8 (2) Day 2 0.8 CD c ΙΓ o r-i OJ Table 3 Effect of PGFgg when Injected Subcutaneous! y on Days , 5 and 6 Example 3 Subcutaneous administration of pharmaceutical preparat i on PGF20; is made up in steri le physiological sal ine at a concentration of 10 mg./ml . and used for subcutaneous administration in female rabbits.

Mature virgin Dutch rabbits weighing about 1.5 kg. each are used. Each of ten females is mated twice with two different proven males and the day of finding sperm in the vaginas of the female rabbits is Day 1. Thereafter, subcutaneous injections are begun on Day 4 with the mated animals divided into five groups each.

In Group I each rabbit receives two subcutaneous injections per day of the pharmaceutical preparation providing a total dai ly dosage of 5 mg./kg ./day of the PGF2a. In Group I I each of the five mated female rabbits receives two l ike dai ly injections subcutaneous 1 y of 0.5 ml . of physiological sal ine.

The injections are given on each of five days and thereafter on Day 12 the animals are sacrificed and autopsied. In none of the rabbits injected with the PGF2 preparation are implantation sites found at autopsy. I n the other group of saline-treated controls four of the rabbits have implantation sites with the number of implants being respectively 8, > 8 and 8. The fifth animal in this group shows no evidence of implantation sites.

Example Intravaginal administration of suppository PGFaa is made up in a suppository base containing two parts by weight of polyethylene glycol 6000 and one part by weight of polyethylene glycol 1 00, The suppositories are formed into pellets with a volume of approximately 1 ml.

The suppositories for administration of the prostaglandin contain 8 mg. each of the PGF2a prostaglandin material.

Ten female rabbits are each mated twice with two different proven males and the day of finding of sperm in the vagina is taken as Day 1. Each rabbit is treated once on days , 5,6, J, and 8 for a total of five days. Since the individual rabbits weight about 1.6 kg., the dosage of the prostaglandin material in the medi cament- treated animals In none of the five prostaglandin-treated rabbits are implantation sites found upon autopsy on Day 12. In each of the five control rabbits treated with saline there are implantation sites averaging 6, 5, > 7 and 9 sites respectively.

Example 5 Aqueous solution Mature female rhesus monkeys (5-6 kg.) are mated naturally at a time and for a duration of the reproductive cycle calculated to maximize the chances of conception. The day of ovulation is determined by fol lowing peripheral blood progestin levels, and ovulation is conf i rmed by laparotomy. Prostaglandin F2a mg./ml. with a sterile aqueous methy Ice 11 u 1 ose vehicle (0.25*). This prostaglandin preparation is injected subcutan-eously b.i.d., 30 mg./day for 5 days. Injection is initiated on Day 7 after the presumed day of ovulation in one animal, female No. 16-M. The other three test animals are injected on Days 11 to 1 post ovulation. Peripheral plasma progestin levels are followed during the cycle current to the time of injection. Pregnancy is diagnosed by rectal palpation to determine uterine enlargement. All test animals are observed for systemic signs of drug toxicity during the course of the experiment .

Peripheral blood progestin levels are not completely depressed by initiating prostaglandin injection on Day 7.

However, progestin levels fall precipitously almost to non-detectable levels in three test animals following the i n i t i at i on of drug injection on Day 11. This drop in progestin level is fol 1 owed by onset of menses on the.2nd, 3rd and ½th day of injection. One of the four test animals, No. 2-M is diagnosed pregnant 0 days after mating. Previous control ferti lity and a confirmed pregnancy in a concurrent control animal indicate planned mating under the conditions of this experiment results in a 7 -80$ ferti lity rate.

No systemic signs of drug toxi ci ty are noted i n any of the animals in the present experiment. Slight tissue necrosis at some of the injection sites and a general tightening of the skin in the local area of i nject i on are noted.

Example 6 Steri le Aqueous Suspension A ster i le veh i cle is prepared to conta i n in each mi 11 i 1 i ter 30 mg. of polyethylene glycol 400 U.S. P. and 2.9 mg. of preservative. Steri 1 izati on i s accomplished by filtration thru a sterile clar i fyi ng pad . 2.2 liters of suspension is prepared to contain 400 mg. per ml. of the acetate of PGFiOt.

Each ml . Tota 1 Acetate of PGFi Sterile, micronized 400 mg . 898 Gm.

Steri le Vehicle I496 Gm.

Add the sterile acetate to about 95^ of the required vehicle until a smooth suspension is obtained. Add the balance of the sterile vehicle and mix well. Pass the whole thru a steri le mill and collect in a sterile container.

Intramuscular injection of 1 ml. to the ovulating human 1 day after coitus during the fertile period is followed by menses at the usual time.

The acetate is replaced by the butyrate, propionate or aforesaid similar acylate or by the methyl, ethyl or similar ester of PGFict with like results.

Example 7 Sterile Aqueous Solution A sterile aqueous solution for intravenous infusion administration is prepared from the following ingredients to contain 25 mg. per ml. of the sodium salt of PGF3 .

Sodium PGF3a 2 Gm.

Lactose Hydrous 50 Gm.

Sodium Bi phosphate anhydrous 1.6 Gm.

Sodium Phosphate Exsiccated 7.5 Gm.

Water for injection q.s. ad 1000 ml.

One milliliter is administered by intravenous infusion to the ovulating human female after intercourse during the fertile period of the cycle. The infusion is given two days before expected onset of menses. It can be repeated on the day before expected menses. Lesser amounts of the active ingredient can be used for infusions given on three or four days or on several days. Thereafter menses occurs at the usual time in Example 8 Intravaginal Suppository I ntravagina 1 supposi tories are prepared to contain in each suppository 0 mg. of prostaglandin ?&Ψ∑ . One thousand suppositories are prepared by mouldit.g a mixture of the fol lowing ingredients: PGF2a, micronized 250 Gm.

Polyethylene glycol 6000 6 0 Gm.

Lactose 100 Gm.

Starting on the second day post-ovu 1 at i on one suppository is used intravaginal ly each day in the ovulating human female with the result that menses occurs on the 28th day of a normal 28-day menstrual cycle.

Example 9 Intravaginal Device An intravaginal device in the form of a toroid is prepared to contain 700 mg. of dihydro PGFi dispersed in the toroid.

The prostagl and i n- type active ingredient is dispersed throughout a vuicanizable polysi loxane polymer which is then moulded in a ring structure to provide a toroid for placement in the vaginal tract. The toroid ring structure is inserted into the vagina after ovulation where it releases the active ingredient and exerts its beneficial biological effect with menses fol lowing at the expected time in the menstrual cycle. At that time the intravaginal device is removed. Like results are obtained with an annular ring coated with the prostaglandin. Example 10 Sublingual Administration One thousand tablets are prepared from the fol lowing ingredients, each containing 50 mg. of active ingredient.

PGF2a, micronized 50 Gm.

Polyethylene' glycol ^000, powdered 150 Gm.

Polyethylene glycol 6000, powdered 75 Gm.

The materials are mixed wel l and compressed into sublingual-type tablets of the proper weight. At the time of ovulation the human female uses one under the tongue and one dai ly thereafter to ensure that menses wi l1 occur at the end of the normal menstrual cycle in the particular female.

Example 11 Sterile Aqueous Solution A sterile aqueous solution containing in each milli liter 50 mg. of PGF3ct is prepared from the following ingredients: PGF3 50 Gm.

Ethanol 300 ml.

Water for injection q.s. ad 1000 ml.

The PGF3 is dissolved in the ethanol and then carefully diluted with the sterile water for injection. Thereafter the whole is steri lized by steri le fi ltration. One milli liter injected intravenously into an ovulating bitch on the 10th and 15th days after sexual contact with a known ferti le stud is beneficial in insuring that the usual heat period wi 11 take place in the bitch indicating that pregnancy is prevented.

Other embodiments in the various dosage unit forms are prepared with the additional compounds represented by the formula heretofore described and used with like beneficial results in the control of the reproductive cycle.

A beneficial additional active ingredient which however is not necessary in the embodiments of the inventive concept is an estrogenic substance, i.e., a naturally occuring or synthetic substance known in the art to evoke typical changes in the accessory sex organs of females; namely, thickening of vaginal mucosa, hypertrophy of the myometriium and proliferation of the endometrium. I llustratively, these substances are estriol, estrone, estradiol, estradiol cyclopentylpropionate, estrogenic substances conjugated, ethinyl estradiol, ethinyl estradiol j5-methyl ether, piperazine estrone sulfate, benzesterol, dienesterol, d i ethy 1 st i 1 besterol d i prop i onate, hexesterol, metha 1 lenst r il and the 1 i k „ These are used in amounts known in the art to be sufficient to provide the afore said typical changes.

Claims (1)

1. 2550 - 1- A pharmaceutical preparation in dosage unit form consisting essentially of an effective amount for controlling the reproduc-tive cycle in an ovulating female mammal of a member selected from the group consisting of the free acids pharmaceutically acceptable salts, acylates wherein the acyl radical is that of a hydrocarbon carboxylic acid having 1 to 8 carbon atoms, inclusive, and carboxylate esters having 1 to 8 carbon atoms, inclusive of a compound represented by the formula wherein X i s CH2CH2 or trans CH=CH and both Y and Z are CH2CH2; X is trans CH=CH, Y is cis CH=CH and Z is CH2CH2 or cis CH=CH; m is 0, 1 or 2 and n is 2, 3, 't or 5, compounded with pharma-ceutical means which adapt the form for systemic administration, said form containing an amount of said member designed to pro-vide to said female mammal from about 0. 01 mg. to about 20 mg./kilo of body weight of said female mammal. - 2- The pharmaceutical preparation of claim 1 which is in the form of a sterile aqueous suspension containing an effective amount up to about 500 mg. per milliliter of said member. - 3- The preparation of claim 1 which is in the form of a sterile oil preparation containing an effective amount up to about 500 mg, per ml. of said member. 4. The preparation of Claim 1 which is in the form of a dosage unit for intravaginal administ ation containing an effective amount up to about 500 mg. of said member* 5 · The pharmaceutical preparation of Claim 1 which is in the form of a dosage unit for sublingual or buccal administration containing an effective amount up to about 200 mg. of said member. 6. The pharmaceutical preparation of Claim 1 aqueous which is in the form of a sterile/solution containing an effective amount up to about 50 mg. per ml. of said member. 7 · A pharmaceutical preparation in dosage unit form for controlling the reproductive cycle in an ovulating female human comprising as active ingredient about 200 mg to about 500 mg of a member selected from the group consisting of the free acids, pharmaceutically acceptable salts, acylates wherein the acyl radical is that of a hydrocarbon carboxylic acid having 1 to 8 carbon atoms, inclusive, and carboxylate esters having 1 to 8 carbon atoms, inclusive of a compound represented by the formula wherein X is CH2CH2 or trans CH=CH and both Y and Z are CHgCH^ X is trans CH=CH, Y is cis CH=CH and Z J is CHgCH2 or cis CH=CH m is O, 1 or 2 and n is 2, 3, 4 or 5» compounded with pharmaceutical means which adapt the form for systemic administration* 8. The pharmaceutical preparation of Claims 1, 2, 31 , 5, ar 6 wherein the member is PGF^-. 9. The pharmaceutical preparation of Claim 7» wherein the member is PGF^^-. 10. Pharmaceutical preparations for controlling the reproductive cycle of ovulating female mammals, substantially as herinbefore described and with reference to any of the Exampftes,